Impact of TP53 Mutations on EGFR-Tyrosine Kinase Inhibitor Efficacy and Potential Treatment Strategy

Fu, Jing; Tong, Yuyang; Xu, Ziguang; Li, Yaonan; Zhao, Yupei; Wang, Tao; Li, Cuidan; Cang, Shundong

doi:10.1016/j.cllc.2022.08.007

Cited by 9 publications

(5 citation statements)

References 39 publications

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“…Cross analysis between these two groups yielded three cancer‐related signal pathways (Figure 3C). It has been reported that the p53 signaling pathway is involved in EGFR TKI resistance and concomitant EGFR and TP53 mutations have a poorer prognosis with EGFR TKI treatment 9–13 . In this study, the VPA‐sensitive cell lines such as PC9, HCC827, and H1975 are EGFR/TP53 co‐mutation while VPA‐insensitive cell lines such as A549 and H1299 cells are EGFR wild type and p53 wildtype or null.…”

Section: Resultsmentioning

confidence: 72%

“…Studies have shown that concurrent TP53 mutation was associated with faster resistance to EGFR‐TKIs and poorer outcomes in EGFR‐mutant lung cancer patients 9–13 . To investigate that whether VPA combined with EGFR‐TKIs could forestall acquired resistance or increased the sensitivity to EGFR‐TKIs, in vitro and in vivo models of EGFR‐mutant lung cancers with acquired resistance to EGFR‐TKIs were first established.…”

Section: Discussionmentioning

confidence: 99%

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Valproic acid increased the efficacy of EGFR TKIs on EGFR/TP53 co‐mutated lung cancers and downregulated mutant‐p53 levels

Hu,

Cheng,

Yang

et al. 2023

Molecular Carcinogenesis

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The TP53 tumor suppressor is the most frequently mutated gene in human cancers. For p53‐targeted therapy, one of the strategies was targeting mutant p53 for degradation. In EGFR‐mutated lung cancer patients, concurrent TP53 mutation was associated with faster resistance to EGFR‐TKIs. In this study, we discovered that valproic acid (VPA), a widely prescribed antiseizure medication, had a synergic effect on sensitive as well as acquired resistant lung cancers with EGFR/TP53 co‐mutation in combination with EGFR‐TKIs. In both in vitro and in vivo models, VPA greatly improved the efficacy of EGFR‐TKIs, including forestalling the occurrence of acquired resistance and increasing the sensitivity to EGFR‐TKIs. Mechanistically, VPA dramatically promoted degradation of mutant p53 in both sensitive and acquired resistant cells while inhibited mutant TP53 mRNA transcription only in sensitive cells. Together, this study suggested that VPA combination treatment could have beneficial effects on EGFR‐mutant lung cancers with concurrent p53 mutation in both early and late stages, expanding the potential clinical applications for VPA.

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Section: Resultsmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Valproic acid increased the efficacy of EGFR TKIs on EGFR/TP53 co‐mutated lung cancers and downregulated mutant‐p53 levels

Hu,

Cheng,

Yang

et al. 2023

Molecular Carcinogenesis

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“…Targeted therapy combined with chemotherapy can afford considerable survival benefits in patients with TP53 mutations and a poor prognosis. Moreover, TP53 mutations can shorten the relapse time in postoperative patients who are more likely to benefit from targeted therapy combined with chemotherapy (12). Herein, the postoperative pathology of the patient indicated carcinosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant osimertinib and chemotherapy for stage IIIA primary pulmonary carcinosarcoma with EGFR 19DEL mutation: A case report

Wang

et al. 2023

Front. Oncol.

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Epidermal growth factor receptor (EGFR) mutations have been frequently detected in patients with pulmonary adenocarcinoma. EGFR Exon 19Del and 21L858R mutations are the two most common EGFR mutations. EGFR-tyrosine kinase inhibitors (TKIs) are widely employed to treat patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Recently, there has been rapid growth in clinical trials assessing neoadjuvant targeted therapy, indicating good application prospects owing to high efficiency and low toxicity. Herein, we discuss the case of a 56-year-old male patient who was initially diagnosed with stage IIIA pulmonary adenocarcinoma (AJCC,8th edition) of the left lower lung with an EGFR Exon 19Del mutation. The patient was treated with osimertinib but failed to undergo timely review and surgery. Subsequently, the patient underwent two cycles of neoadjuvant chemotherapy (NAC) combined with neoadjuvant targeted therapy. After the tumor load and size had significantly decreased, radical surgery was successfully performed under thoracoscopy. However, postoperative pathology revealed carcinosarcoma, pT2aN0M0, stage IB, and the pathological response was 50%. The present case report provides practical clinical evidence for the application of neoadjuvant targeted therapy combined with chemotherapy for locally advanced primary pulmonary carcinosarcoma with EGFR mutation.

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“…Moreover, the combination of afatinib and vinorelbine achieves the clinical benefit in HER2‐positive breast cancer patients, which is accompanied by frequent p53 gain‐of‐function mutations 9 . Furthermore, it has been observed that EGFR TKI therapy is beneficial for p53 wild‐type lung cancer patients 10 . Therefore, we speculated that the regimen of afatinib and vinorelbine might be suitable for p53 wild‐type NSCLC patients.…”

Section: Introductionmentioning

confidence: 97%

“…9 Furthermore, it has been observed that EGFR TKI therapy is beneficial for p53 wild-type lung cancer patients. 10 Therefore, we speculated that the regimen of afatinib and vinorelbine might be suitable for p53 wild-type NSCLC patients. Given the efficacy and side effects of the combination of afatinib and vinorelbine, 5 an alternative adjuvant strategy may be needed.…”

mentioning

confidence: 99%

Aspirin boosts the synergistic effect of EGFR/p53 inhibitors on lung cancer cells by regulating AKT/mTOR and p53 pathways

Liu,

Cui,

Wang

et al. 2023

Cell Biochemistry & Function

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The regimen of afatinib and vinorelbine has been used to treat breast or lung cancer cells with some limitations. Aspirin alone or in combination with other agents has shown unique efficacy in the treatment of cancer. We designed a preclinical study to investigate whether the triple therapy of aspirin, afatinib, and vinorelbine could synergistically inhibit the growth of p53 wild‐type nonsmall cell lung cancer (NSCLC) cells. Three NSCLC cells A549, H460, and H1975 were selected to study the effect of triple therapy on cell proliferation and apoptosis. Compared to single agents, triple therapy synergistically inhibited the proliferation of lung cancer cells with combination index <1. Meanwhile, the therapeutic index of triple therapy was superior to that of single agents, indicating a balance between efficacy and safety in the combination of three agents. Mechanistic studies showed that triple therapy significantly induced apoptosis by decreasing mitochondrial membrane potential, increasing reactive oxygen species, and regulating mitochondria‐related proteins. Moreover, epidermal growth factor receptor (EGFR) downstream signaling proteins including JNK, AKT, and mTOR were dramatically suppressed and p53 was substantially increased after NSCLC cells were exposed to the triple therapy. We provided evidence that the triple therapy of aspirin, afatinib and vinorelbine synergistically inhibited lung cancer cell growth through inactivation of the EGFR/AKT/mTOR pathway and accumulation of p53, providing a new treatment strategy for patients with p53 wild‐type NSCLC.

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Impact of TP53 Mutations on EGFR-Tyrosine Kinase Inhibitor Efficacy and Potential Treatment Strategy

Cited by 9 publications

References 39 publications

Valproic acid increased the efficacy of EGFR TKIs on EGFR/TP53 co‐mutated lung cancers and downregulated mutant‐p53 levels

Valproic acid increased the efficacy of EGFR TKIs on EGFR/TP53 co‐mutated lung cancers and downregulated mutant‐p53 levels

Neoadjuvant osimertinib and chemotherapy for stage IIIA primary pulmonary carcinosarcoma with EGFR 19DEL mutation: A case report

Aspirin boosts the synergistic effect of EGFR/p53 inhibitors on lung cancer cells by regulating AKT/mTOR and p53 pathways

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